DESCRIPTION (Investigator's Abstract): N-Hydroxy-L-arginine (NHA) is an intermediate in the biosynthesis of nitric oxide (NO) from the amino acid L-arginine. This reaction is catalyzed by the enzyme nitric oxide synthase (NOS). Early enzymological work using purified NOS indicated that NHA was not released during enzyme turnover and therefore should not reach significant intracellular concentrations. However, more recent data in whole cell experiments indicates that, contrary to previous beliefs, NHA is released by NOS and can then leave the cell and reach extremely high levels in extracellular space. As it is unlikely that this phenomenon represents an inherent inefficiency in NO biosynthesis, NHA must serve a physiological function. Since NHA release has been found to be significant from the NOS isoform which is induced during infection or parasite invasion, it is likely that NHA is involved in the immune response. Thus, the goal of this proposal is to investigate the physiological role of NHA in the immune response. Preliminary data indicate that NHA may serve to inhibit cell proliferation by several mechanisms based on its interaction with the enzyme arginase. An understanding of the mechanism of action of NHA may lead to the development of novel and unique strategies for the treatment of infection or cancer.